title: Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas.
abstract: Recently, a group of microRNAs (miRNAs) were shown to be dysregulated in gliomas, and involved in glioma development. However, the effect of miRNA-miRNA functional networks on gliomas is poorly understood. In this study, we identified that FBJ murine osteosarcoma viral oncogene homolog (FOS)-mediated miR-181b/miR-21 signalling was critical for glioma progression. Using microarrays and quantitative RT-PCR (qRT-PCR), we found increased FOS in high grade gliomas. FOS depletion (via FOS-shRNA), inhibited invasion and promoted apoptosis in glioma cells. Using microarrays, combined with Pearson correlation analysis, we found FOS positively correlated with miR-21 expression. Reduction of FOS inhibited miR-21 expression by binding to the miR-21 promoter using luciferase reporter assays. Introduction of miR-21 abrogated FOS knockdown-induced cell invasion and apoptosis. Moreover, bioinformatics and luciferase reporter assays showed that miR-181b modulated FOS expression by directly targeting the binding site within the 3'UTR. Expression of FOS with a FOS cDNA lacking 3'UTR overrided miR-181b-induced miR-21 expression and cell function. Finally, immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis revealed a significant correlation in miR-181b, FOS and miR-21 expression in nude mouse tumour xenograft and human glioma tissues. To our knowledge, it is the first time to demonstrate that miR-181b/FOS/miR-21 signalling plays a critical role in the progression of gliomas, providing important clues for understanding the key roles of transcription factor mediated miRNA-miRNA functional network in the regulation of gliomas.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Luo
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Jiajia
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Junxia
authors.initials: J
authors.lastname: Zhang
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Yu
authors.initials: Y
authors.lastname: Yin
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C064269:FOSB protein, human; C524940:MIRN21 microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos
keywords: AP-1; FOS; Glioma; miR-181b; miR-21